The invention relates to compounds of Formula II and XII, process of preparation and use in preparation of piclidenoson thereof,
, and .

The present invention also provides solid forms of piclidenoson and process of preparation thereof.

BACKGROUND OF THE INVENTION
The compound, N6-(3-iodobenzyl)-adenosine N-methyluronamide i.e. piclidenoson is used for the treatment of variety of autoimmune-inflammatory disorders, particularly arthritis. It is represented by structure represented as Formula I:
.

Piclidenoson of Formula I is disclosed in US patent 5,773,423. US 5,773,423 further discloses the synthesis of compound of Formula I as shown in Scheme-1 below:

Scheme-1:
.

US 9,102,698 discloses the synthesis of piclidenoson of Formula I as shown in scheme-2 below:
Scheme-2:
.
Although there is a literature known in the prior published references that discloses process for preparing piclidenoson, however the present invention emphasis on less complex process for the preparation of piclidenoson using novel compounds as intermediates.

OBJECT OF THE INVENTION
The main object of the present invention is to provide compounds of Formula II, and XII;
, and .

Another object of the present invention is to provide a process for preparing piclidenoson by using compounds of Formula II and/or Formula XII.

Another object of the present invention is to provide various solid forms of piclidenoson wherein said solid forms includes amorphous, crystalline and amorphous solid dispersion of piclidenoson.

SUMMARY OF THE INVENTION
In first aspect, the present invention provides compounds of Formula II,

wherein, R1 is selected from hydrogen, carbon and silyl containing moieties;
G is selected from -CH2 and C=O;
R2, R3 are independently selected from hydrogen, substituted straight and branched alkyl chain, unsubstituted straight and branched alkyl chain, substituted and unsubstituted aryl, substituted and unsubstituted alkaryl, silyl containing moieties; and
optionally R2 and R3 together represents substituted and unsubstituted cyclic ring, wherein when R1 is hydrogen, the dotted bond is represented as a solid covalent bond and “N” is attached to aliphatic carbon with double bond.

In another aspect, the compound of Formula II is represented as compound of Formula III, wherein R2 and R3 is selected from hydrogen, “N” is attached to aliphatic carbon with single bond i.e. dotted bond is absent, and R1 and G are as defined above.
.

In another aspect, the compound of Formula II is represented as compound of Formula IV, wherein R2 and R3 together represents substituted cyclic ring, G is –CH2, “N” is attached to aliphatic carbon with single bond i.e. dotted bond is absent, and R1 is as defined above,
.

In another aspect, the present invention provides compound of Formula II represented as compound of Formula VI, wherein G is –CH2, R1 is hydrogen, R2 and R3 are hydrogen, and dotted bond is a solid bond, wherein “N” is connected with aliphatic carbon by a double bond,
.

In another aspect, the present invention provides compound of Formula II represented as compound of Formula VII, wherein G is carbonyl, R1 is hydrogen, R2 and R3 is hydrogen, and dotted bond is a solid bond, wherein “N” is connected with aliphatic carbon by a double bond,
.

In another aspect, the present invention provides a process for the preparation of piclidenoson compound of Formula I,
,
comprising the steps of:
a) reacting compound of Formula VIIIa with compound of Formula IX in presence of a suitable solvent to get compound of Formula II,
,
wherein R1, R2, R3, G are as defined above, and L is a leaving group; and
b) converting compound of Formula II to piclidenoson of Formula I.

In another aspect, the present invention provides a process for the preparation of piclidenoson compound of Formula I,
,
comprising the steps of:
a) protecting diol of compound of Formula IIIa with diol protecting reagent to get compound of Formula II,
,
wherein R1 and G are as defined above, and
R2 and R3 are independently selected from substituted straight and branched alkyl chain, unsubstituted straight and branched alkyl chain, substituted and unsubstituted aryl, substituted and unsubstituted alkaryl, silyl containing moieties, and optionally R2 and R3 together represents substituted and unsubstituted cyclic ring; and
b) converting compound of Formula II to piclidenoson of Formula I.

In another aspect, the present invention provides a process for the preparation of piclidenoson, comprising the steps of:
a) adding 2-(6-amino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol of Formula X and 3-iodobenzaldehyde in a suitable solvent to give 2-(hydroxymethyl)-5-(6-((3-iodobenzylidene)amino)-9H-purin-9-yl)tetrahydrofuran-3,4-diol of Formula VI,
; and
b) converting compound of Formula VI to piclidenoson of Formula I.

In another aspect, the present invention provides a process for the preparation of piclidenoson, comprising the steps of:
a) adding 5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-carboxylic acid of Formula XI and 3-iodobenzaldehyde in a suitable solvent to give 3,4-dihydroxy-5-(6-((3-iodobenzylidene)amino)-9H-purin-9-yl)tetrahydrofuran-2-carboxylic acid of Formula VII,
; and
b) converting compound of Formula VII to piclidenoson of Formula I.

In another aspect, the present invention provides a compound of Formula XII,
.

In another aspect, the present invention provides a process for the preparation of piclidenoson, comprising the steps of:
a) adding 9H-purin-6-amine of Formula XIII and 3-iodobenzaldehyde in a suitable solvent to give (E)-1-(3-iodophenyl)-N-(9H-purin-6-yl)methanimine of Formula XII,
; and
b) converting compound of Formula XII to piclidenoson of Formula I.

In another aspect, the present invention provides amorphous and crystalline form of piclidenoson.

In another aspect, the present invention provides amorphous solid dispersion of piclidenoson with pharmaceutically acceptable excipients thereof.

In another aspect, the present invention provides a process for the preparation of amorphous solid dispersion of piclidenoson comprising the steps of:
a) providing a solution of piclidenoson in a suitable solvent;
b) providing atleast one pharmaceutically acceptable excipient in a solvent and adding the solution obtained in step a); and
c) isolating the amorphous solid dispersion of piclidenoson.

DETAILED DESCRIPTION
In one embodiment, the present invention provides compounds of Formula II,

wherein, R1 is selected from hydrogen, carbon and silyl containing moieties;
G is selected from -CH2 and C=O;
R2, R3 are independently selected from hydrogen, substituted straight and branched alkyl chain, unsubstituted straight and branched alkyl chain, substituted and unsubstituted aryl, substituted and unsubstituted alkaryl, silyl containing moieties; and
optionally R2 and R3 together represents substituted and unsubstituted cyclic ring, wherein when R1 is hydrogen, the dotted bond is represented as a solid covalent bond and “N” is attached to aliphatic carbon with double bond.

In one preferred embodiment, the compound of Formula II is represented as compound of Formulae III, IV, VI and VII;
,
, and
wherein R1 and G are as defined above.

In another embodiment, the present invention provides a process for the preparation of piclidenoson compound of Formula I,
,
comprising the steps of:
a) reacting compound of Formula VIIIa with compound of Formula IX in presence of a suitable solvent to get compound of Formula II,
,
wherein R1, R2, R3, G are as defined above, and L is a leaving group; and
b) converting compound of Formula II to piclidenoson of Formula I.

In another embodiment, the present invention provides a process for the preparation of piclidenoson compound of Formula I,
,
comprising the steps of:
a) protecting diol of compound of Formula III with diol protecting reagent to get compound of Formula II,
,
wherein R1, and G are as defined above, and
R2 and R3 are independently selected from substituted straight and branched alkyl chain, unsubstituted straight and branched alkyl chain, substituted and unsubstituted aryl, substituted and unsubstituted alkaryl, silyl containing moieties, and optionally R2 and R3 together represents substituted and unsubstituted cyclic ring; and
b) converting compound of Formula II to piclidenoson of Formula I.

In another embodiment, the present invention further provides a process for the preparation of piclidenoson of Formula I, comprising the steps of:
a) adding 6-chloro-9H-purine of Formula XVII and (3-iodophenyl)methanamine of Formula XVIII to get N-(3-iodobenzyl)-9H-purin-6-amine of Formula VIII,
;
b) reacting N-(3-iodobenzyl)-9H-purin-6-amine of Formula VIII with compound of Formula IX in presence of a suitable solvent to get compound of Formula IIa,
,
wherein, R1 is selected from carbon and silyl containing moieties,
R2 and R3 are independently selected from substituted straight and branched alkyl chain, unsubstituted straight and branched alkyl chain, substituted and unsubstituted aryl, substituted and unsubstituted alkaryl, silyl containing moieties, and optionally R2 and R3 together represents substituted and unsubstituted cyclic ring,
G is –CH2,
L is a leaving group selected from tosylate, mesylate, alkoxy, acetoxy, and halogen, and
wherein, in compound of Formula IIa, N is connected to aliphatic carbon by single bond;
c) deprotecting the compound of Formula IIa in presence of suitable solvent to get compound of Formula XIX,
,
wherein G is CH2;
d) oxidizing the compound of Formula XIX in presence of suitable oxidising agent to get compound of Formula XX,
;
e) amidating the compound of Formula XX in presence of methyl amine to get compound of Formula XXI,
;
f) deprotecting the compound of Formula XXI to give piclidenoson of Formula I,
; and
g) optionally purifying the piclidenoson of Formula I.

In another embodiment, the present invention provides a process for the preparation of piclidenoson, comprising the steps of:
a) adding 2-(6-amino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol of Formula X and 3-iodobenzaldehyde in a suitable solvent to give 2-(hydroxymethyl)-5-(6-((3-iodobenzylidene)amino)-9H-purin-9-yl)tetrahydrofuran-3,4-diol of Formula VI,
; and
b) converting compound of Formula VI to piclidenoson of Formula I.

In another embodiment, the present invention provides a process for the preparation of piclidenoson, comprising the steps of:
a) adding 2-(6-amino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol of Formula X and 3-iodobenzaldehyde in a suitable solvent to give 2-(hydroxymethyl)-5-(6-((3-iodobenzylidene)amino)-9H-purin-9-yl)tetrahydrofuran-3,4-diol of Formula VI,
;
b) reducing 2-(hydroxymethyl)-5-(6-((3-iodobenzylidene)amino)-9H-purin-9-yl)tetrahydrofuran-3,4-diol of Formula VIII in presence of reducing agent to give compound of Formula XXII,
;
c) protecting compound of Formula XXII with diol protecting reagent to give compound of Formula XIX,
,
wherein R2 and R3 are independently selected from substituted straight and branched alkyl chain, unsubstituted straight and branched alkyl chain, substituted and unsubstituted aryl, substituted and unsubstituted alkaryl, silyl containing moieties, and optionally R2 and R3 together represents substituted and unsubstituted cyclic ring; and
d) converting compound of Formula XIX to piclidenoson of Formula I.

In another embodiment, the present invention further provides a process for the preparation of piclidenoson, comprising the steps of:
a) adding 5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-carboxylic acid of Formula XI and 3-iodobenzaldehyde in a suitable solvent to give 3,4-dihydroxy-5-(6-((3-iodobenzylidene)amino)-9H-purin-9-yl)tetrahydrofuran-2-carboxylic acid of Formula VII,
; and
b) converting compound of Formula VII to piclidenoson of Formula I.

In another embodiment, the present invention further provides a process for the preparation of piclidenoson, comprising the steps of:
a) adding 5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-carboxylic acid of Formula XI and 3-iodobenzaldehyde in a suitable solvent to give 3,4-dihydroxy-5-(6-((3-iodobenzylidene)amino)-9H-purin-9-yl)tetrahydrofuran-2-carboxylic acid of Formula VII,
;
b) reducing compound of Formula VII in presence of suitable reducing agent to get 3,4-dihydroxy-5-(6-((3-iodobenzyl)amino)-9H-purin-9-yl)tetrahydrofuran-2-carboxylic acid of Formula XXIII,
;
c) protecting compound of Formula XXIII with diol protecting agent to get compound of Formula XX,
,
wherein R2 and R3 are independently selected from substituted straight and branched alkyl chain, unsubstituted straight and branched alkyl chain, substituted and unsubstituted aryl, substituted and unsubstituted alkaryl, silyl containing moieties, and optionally R2 and R3 together represents substituted and unsubstituted cyclic ring; and
d) converting compound of Formula XX to piclidenoson of Formula I.

In one another embodiment, the present invention provides a compound of Formula XII,
.

In another embodiment, the present invention further provides a process for the preparation of piclidenoson, comprising the steps of:
a) adding 9H-purin-6-amine of Formula XXIV and 3-iodobenzaldehyde in a suitable solvent to give 1-(3-iodophenyl)-N-(9H-purin-6-yl)methanimine of Formula XII,
; and
b) converting compound of Formula XVIII to piclidenoson of Formula I.

In further embodiment, the present invention provides a process for the preparation of piclidenoson of Formula I,

comprising the steps of:
a) adding 9H-purin-6-amine of Formula XXIV and 3-iodobenzaldehyde in a suitable solvent to give 1-(3-iodophenyl)-N-(9H-purin-6-yl)methanimine of Formula XII,
;
b) hydrogenating 1-(3-iodophenyl)-N-(9H-purin-6-yl)methanimine of Formula XII in presence of hydrogenating agent to give N-(3-iodobenzyl)-9H-purin-6-amine of Formula VIII,
; and
c) converting compound of Formula VIII to piclidenoson of Formula I.

In one another embodiment, the base used in the preparation of piclidenoson and intermediates thereof is selected, but not limited to, the group comprising of organic and inorganic bases such as sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide, pyridine, triethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, cesium bicarbonate, magnesium carbonate, dimethyl amino pyridine, aniline, N,N-dimethyl aniline, diisopropylethylamine, diisopropyl amine, diethyl amine, dimethyl amine and the like.

In one another embodiment, the suitable reducing agent used in the process of the present invention includes, but not limited to, sodium borohydride, Pd/C and H2, Palladium hydroxide/H2, raney nickel and the like.

In seventh embodiment, the present invention provides amorphous and crystalline form of piclidenoson.

The amorphous form of piclidenoson is substantially free of crystalline form wherein said amorphous form is characterized by having crystalline form which is less than equal to 10% w/w, preferably 5%w/w and less; and most preferably, 1% w/w and less.

In eighth embodiment, the present invention provides amorphous solid dispersion of piclidenoson with pharmaceutically acceptable excipients thereof.

In another embodiment, the present invention provides a process for the preparation of amorphous solid dispersion of piclidenoson comprising the steps of:
a) providing a solution of piclidenoson in a suitable solvent;
b) providing atleast one pharmaceutically acceptable excipient in a solvent and adding the solution obtained in step a); and
c) isolating the amorphous solid dispersion of piclidenoson.

In further embodiment, the piclidenoson described herein, for the preparation various amorphous solid dispersion are amorphous, or crystalline in nature. Even the reaction mixture containing piclidenoson can be used for preparing solid dispersions.

In further embodiment, pharmaceutically acceptable excipient may include, but not limited to water soluble and water insoluble polymer.

In another embodiment, the solvent(s) used in the preparation of piclidenoson, intermediates and solid forms thereof is selected from, but not limited to, the group comprising of alcohols, ketones, esters, amides, halogenated solvents, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, pyrrolidones, sulfoxides, amides, water and mixture thereof. Preferably the solvent is selected from the group comprising of toluene, xylene, dimethyl acetamide, dimethyl formamide, N-methyl pyrrolidine, dimethyl sulfoxide, hexamethyl phosphoramide, tetrahydrofuran, dioxane, methyl-tetrahydrofuran, diethyl ether, isopropyl ether, isobutyl acetate, methyl tert-butyl ether, acetone, methyl isobutyl ketone, methyl ethyl ketone, methanol, ethanol, methyl tert-butyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, t-butyl acetate, dichloromethane, ethylene dichloride, chloroform, dichlorobenzene, diethyl ether, isopropyl ether, heptane, hexane, pentane, water, C1-C5 straight and branched chain alcohols and mixture thereof.

In another embodiment, the present invention provides piclidenoson of Formula I substantially free of impurities wherein each impurity is less than about 0.3% w/w and total impurity is less than about 1.5% w/w.

In another embodiment, the present invention provides piclidenoson of Formula I substantially free of compounds of Formula II wherein said compound of Formula II is less than about 0.3% w/w.

In another embodiment, the present invention provides substantially pure piclidenoson of Formula I characterized by the purity of 99.0% and above, preferably 99.5% and above, and most preferably 99.9% and above.

In another embodiment, the present invention provides the piclidenoson of Formula I that is characterized by particle size distribution wherein, d90 is 0.1µm to 200µm, preferably d90 is 2.0 µm to 150µm. Preferably, the particle size distribution d90 is not more than 1.0mm.

In another embodiment, the present invention further provides a composition comprising piclidenoson as prepared by the process of the present invention, along with atleast one pharmaceutical acceptable excipients.

In another embodiment, the present invention further provides method of treating collagen induced arthritis and inflammatory bowel disease by administering piclidenoson prepared as per the process of the present invention.

EXAMPLES:

EXAMPLE-1: Synthesis of Piclidenoson:

1.1 Synthesis of 2-(hydroxymethyl)-5-(6-((3-iodobenzylidene)amino)-9H-purin-9-yl) tetrahydrofuran-3,4-diol
To a solution of 2-(6-amino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (10.0 g, 0.03741 mole) in 150.0 ml of ethanol was added 3-iodobenzaldehyde (10.41g, 0.0449 mole) and refluxed for 10.0 hrs. The reaction mixture was evaporated under vacuum to give desired compound.

1.2 Synthesis of 2-(hydroxymethyl)-5-(6-((3-iodobenzyl)amino)-9H-purin-9-yl) tetrahydrofuran-3,4-diol
Charged 2-(hydroxymethyl)-5-(6-((3-iodobenzylidene)amino)-9H-purin-9-yl)tetrahy drofuran-3,4-diol (5.2 g, 0.0108 mole) in methanol (75.0 ml) at RT under inert atmosphere. Cooled the reaction mixture at 0°C and added sodium borohydride (0.84 g, 0.0216 mole) portion wise. The reaction mixture was stirred at ambient temperature for 3-4 hrs. The resulting reaction mixture was poured in to ice cooled water, adjusted pH 3-4 using acetic acid and extracted with ethyl acetate (x2). Combined the organic layer, dried over Na2SO4, filtered and evaporated in vacuum to give the 2-(hydroxymethyl)-5-(6-((3-iodobenzyl)amino)-9H-purin-9-yl)tetrahydrofuran-3,4-diol.

1.3 Synthesis of (6-(6-((3-iodobenzyl)amino)-9H-purin-9-yl)-2,2-dimethyl tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol
Charged 4.2 g (0.00869 mol) of 2-(hydroxymethyl)-5-(6-((3-iodobenzyl)amino)-9H-purin-9-yl)tetrahydrofuran-3,4-diol in dry acetone (20.0 ml) in a round bottom flask. To this solution was added 14.0 mg (0.0869 mol) of para-toluenesulfonic acid (PTSA) and stirred for 1 h under nitrogen at room temperature. Reaction mixture was cooled to 0°C and a saturated solution of NaHCO3 (50 ml) was added and stirred for 5 minutes. The resulting reaction mixture was extracted with ethyl acetate (x2). Combined the organic layer, dried over Na2SO4, filtered and evaporated in vacuum to give desired compound.

1.4 Synthesis of 6-(6-((3-iodobenzyl)amino)-9H-purin-9-yl)-2,2-dimethyl tetrahydrofuro[3,4-d][1,3]dioxole-4-carboxylic acid
Charged (6-(6-((3-iodobenzyl)amino)-9H-purin-9-yl)-2,2-dimethyl tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (3.8 g, 0.00726 mol), (diacetoxyiodo)benzene (7.01 g, 0.0217 mol) and (2,2,6,6-tetramethylpiperidinyl-1-yl)oxyl (TEMPO, 0.226 g, 0.00145 mol) in acetonitrile/DM water (1:1, 38.6 ml). The reaction mixture was stirred at 40°C for 4 hours. The mixture was poured into acetic acid and the product was extracted with ethyl acetate (x2). Combined the organic layer, dried over Na2SO4, filtered and evaporated in vacuum to give desired compound.

1.5 Synthesis of 6-(6-((3-iodobenzyl)amino)-9H-purin-9-yl)-N,2,2-trimethyl tetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide
Charged 6-(6-((3-iodobenzyl)amino)-9H-purin-9-yl)-2,2-dimethyl tetrahydrofuro[3,4-d][1,3]dioxole-4-carboxylic acid (2.0 g, 0.003724 mol), methylamine HCl (0.377 g, 0.00558 mol), Hydroxybenzotriazole (HOBt) (0.754 g, 0.005586 mol), 1-Ethyl-3-dimethylaminopropyl)carbodiimide (EDAC) (0.867 g, 0.00558 mol) and N,N-diisopropylethylamine (2.40 g, 0.01862 mol) in 20 ml of anhydrous DMF/CH2Cl2 (1:1,v/v) and stirred at RT for 12 h. The mixture was diluted with EtOAc, washed with water, and concentrated to dryness to give desired compound.

1.6 Synthesis of Piclidenoson
Charged 6-(6-((3-iodobenzyl)amino)-9H-purin-9-yl)-N,2,2-trimethyl tetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide (1.5 g,0.00272 mol) in 80% aqueous formic acid (20 ml). Stirred the reaction mass at ambient temperature for 12 hours. Evaporated the mixture to give piclidenoson.

EXAMPLE-2: Synthetic of Piclidenoson:

2.1 Synthesis of 3,4-dihydroxy-5-(6-((3-iodobenzylidene)amino)-9H-purin-9-yl)tetrahydrofuran-2-carboxylic acid
Added 5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-carboxylic acid (10.0 g, 0.03558 mole) and 3-iodobenzaldehyde (9.90 g, 0.0427 mole) in ethanol 150.0 ml and refluxed for 10.0 hrs. The reaction mixture was evaporated under vacuum to give desired compound.

2.2 Synthesis of 3,4-dihydroxy-5-(6-((3-iodobenzyl)amino)-9H-purin-9-yl) tetrahydrofuran-2-carboxylic acid
Charged 3,4-dihydroxy-5-(6-((3-iodobenzylidene)amino)-9H-purin-9-yl)tetrahydro furan-2-carboxylic acid (5.2 g, 0.0105 mole) in methanol (75.0 ml) at RT under inert atmosphere. Cooled the reaction mixture at 0°C and added sodium borohydride (0.819 g, 0.0210 mole) portion wise. The reaction mixture was stirred at ambient temperature for 3-4 hrs. Poured the resulting reaction mixture into ice cooled water, adjusted the pH 3-4 using acetic acid and extracted with ethyl acetate (x2). Combined the organic layer and evaporated under vacuum to give desired compound.

2.3 Synthesis of 6-(6-((3-iodobenzyl)amino)-9H-purin-9-yl)-2,2-dimethyl tetrahydrofuro[3,4-d][1,3]dioxole-4-carboxylic acid
3,4-dihydroxy-5-(6-((3-iodobenzyl)amino)-9H-purin-9-yl)tetrahydrofuran-2-carboxylic acid (4.2 g , 0.00845 mol) was dissolved in dry acetone (21.0 mL) in a round bottom flask (100 ml). To this solution was added para-toluenesulfonic acid (PTSA) (14.0 mg 0.0813 mmol) and stirred for 1 h under nitrogen at room temperature. Then the reaction mixture was cooled to 0°C and a saturated solution of NaHCO3 (50 ml) was added and stirred for 5 minutes. The resulting reaction mixture was extracted with ethyl acetate (x2). Combined the organic layer, dried over Na2SO4, filtered and evaporated under vacuum to give desired compound.

2.4 Synthesis of Piclidenoson
Piclidenoson was synthesized by using 6-(6-((3-iodobenzyl)amino)-9H-purin-9-yl)-2,2-dimethyl tetrahydrofuro[3,4-d][1,3]dioxole-4-carboxylic acid as starting material and following similar procedure as that of experiments 1.5 and 1.6.

EXAMPLE-3: Synthesis of Piclidenoson

3.1 Synthesis of 1-(3-iodophenyl)-N-(9H-purin-6-yl)methanimine
Added adenine (10.0 g, 0.07407mole) and 3-iodobenzaldehyde (20.6 g, 0.0888 mole) in ethanol 320.0 ml and refluxed for 10.0 hrs. The reaction mixture was evaporated under vacuum to give desired compound.

3.2 Synthesis of N-(3-iodobenzyl)-9H-purin-6-amine
Charged 1-(3-iodophenyl)-N-(9H-purin-6-yl)methanimine (5.0 g, 0.01432 mole) in methanol (55.0 ml) at RT under inert atmosphere. Cooled the reaction mixture at 0°C and added sodium borohydride (1.11g, 0.0286 mole) portion wise. The reaction mixture was stirred at ambient temperature for 3-4 hrs. The resulting reaction mixture was poured into ice cooled water, adjusted pH to 3-4 using acetic acid and extracted with ethyl acetate (x2). Combined the organic layer, dried over Na2SO4, filtered and evaporated under vacuum to give desired compound.

3.3 Synthesis of 2-(6-((3-iodobenzyl)amino)-9H-purin-9-yl)-5-(methyl carbamoyl)tetrahydrofuran-3,4-diyl dibenzoate
A mixture of 1-(3-iodophenyl)-N-(9H-purin-6-yl)methanimine (2.5 g, 0.007122 mole), ammonium sulfate (5.0 mg) and HMDS (20.0 ml) was refluxed under inert atmosphere for 1.0 hrs. HMDS was removed by rotary evaporation in vacuo. The syrup was dissolved in dry acetonitrile. 1-O-acetyl-2,3,5-tri-O-benzoyl-ß-D-ribofuranoside (3.61 g, 0.00854 mole), potassium nonaflouro-butane sulfonate (12.03g, 0.0356 mole), trichloro silane (2.89 ml, 0.0259 mole) were added to the solution and the reaction mixture was refluxed for 3.0 hrs under nitrogen. Aqueous saturated sodium bicarbonate solution and chloroform were added. After stirring for 1.0 hrs two layers were separated and aqueous layer extracted with chloroform. Organic layer was washed with water, dried over anhydrous MgSO4, filtered, and concentrated to dryness to give desired compound.

3.4 Synthesis of Piclidenoson:
A mixture of 2-(6-((3-iodobenzyl)amino)-9H-purin-9-yl)-5-(methylcarbamoyl)tetrahydrofuran-3,4-diyl dibenzoate (5.0 g, 0.01432 mole) in methanolic ammonia (55.0 ml) was stirred at RT for 48 hrs to give 3,4-dihydroxy-5-{6-[(3-iodobenzyl)amino]-9H-purin-9-yl}-N-methyl tetra hydrofuran-2-carboxamide.

EXAMPLE-4: Synthesis of Piclidenoson:

4.1 Synthesis of N-(3-iodobenzyl)-9H-purin-6-amine:
A mixture of 6-chloropurine (1050 mg), 3-iodobenzylamine (190 mg), and triethylamine (0.27 ml) in absolute ethanol (2 ml) was heated for 24 h at 80° C. After cooling, the resulting solid was filtered under suction, washed with ethyl acetate, and dried to give 191.3 mg of N-(3-iodobenzyl)-9H-purin-6-amine.

4.2 Synthesis of (2R,3R,4S,5R)-2-(6-((3-iodobenzyl)amino)-9H-purin-9-yl)-5-(((triisopropylsilyl)oxy)methyl) tetrahydrofuran-3,4-diol
Equivalent amount of N-(3-iodobenzyl)-9H-purin-6-amine (190 mg) and equivalent amount of (2S,3R,4S,5R)-2-chloro-5-(((triisopropylsilyl)oxy)methyl)tetrahydrofuran-3,4-diol is taken in xylene and catalytic amount of TMSOTF was added and reflux at a temperature of 80-100oC to give (2R,3R,4S,5R)-2-(6-((3-iodobenzyl)amino)-9H-purin-9-yl)-5-(((triisopropylsilyl)oxy)methyl) tetrahydrofuran-3,4-diol.

4.3 Synthesis of 9-((3aR,4R,6R,6aR)-2,2-dimethyl-6-(((triisopropylsilyl)oxy)methyl) tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-N-(3-iodobenzyl)-9H-purin-6-amine:
Added (2R,3R,4S,5R)-2-(6-((3-iodobenzyl)amino)-9H-purin-9-yl)-5-(((triisopropyl silyl) oxy)methyl) tetrahydrofuran-3,4-diol (4.6 g) and 2,2-dimethoxy propane (10.16 ml) in round bottom flask and added dropwise to anhydrous acetone and then added p- toluene sulfonic acid monohydrate (3.18 gm) at room temperature. After completion of the reaction quenched the reaction with saturated sodium bicarbonate solution. The reaction solution was concentrated under reduced pressure and the organic layer was extracted with chloroform (4 × 20 ml) and then washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Separated the resultant and concentrated under reduced pressure to give desired compound.
4.4 Synthesis of ((3aR,4R,6R,6aR)-6-(6-((3-iodobenzyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol
9-((3aR,4R,6R,6aR)-2,2-dimethyl-6-(((triisopropylsilyl)oxy)methyl) tetrahydrofuro [3,4-d][1,3]dioxol-4-yl)-N-(3-iodobenzyl)-9H-purin-6-amine (4 gm) was taken in aqueous methanol (100 ml) and refluxed at a temperature of 50-60oC to give 2.9 gm of desired compound.

4.5 Synthesis of (3aS,4S,6R,6aR)-6-(6-((3-iodobenzyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxylic acid
((3aR,4R,6R,6aR)-6-(6-((3-iodobenzyl)amino)-9H-purin-9-yl)-2,2-dimethyl-tetrahydro furo[3,4-d][1,3]dioxol-4-yl)methanol (2.4) gm was added as a solution in acetonitrile-water to the oxidant mixture in water at 30-35°C for two hours. After completion of reaction, cooled to room temperature and extracted the compound in ethyl acetate and concentrated the organic layer to give the desired compound.

4.6 Synthesis of (3aS,4S,6R,6aR)-6-(6-((3-iodobenzyl)amino)-9H-purin-9-yl)-N,2,2-trimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide
3aS,4S,6R,6aR)-6-(6-((3-iodobenzyl)amino)-9H-purin-9-yl)-2,2-dimethyl-tetrahydro furo[3,4-d][1,3]dioxole-4-carboxylic acid (1.2 gm) was added to a solution of thionyl chloride (0.53 ml) and dimethylformamide (0.26 ml) in anhydrous chloroform (45 ml, dried over Al2O3). The mixture was heated to reflux with the exclusion of moisture for 6 h. After cooling, the solvent was removed in vacuum leaving a syrup that was then dissolved in chloroform (15 ml). The solution was cooled to 0oC and 2 ml of methylamine dissolved in 20 ml of chloroform was added. After stirring for 15 min at <10oC, the solution was extracted successively with HCl (0.1N, 3.times.70 ml), sodium bicarbonate (0.5M, 110 ml), and then water (2.times.50 ml). The organic layer was dried (over MgSO4), filtered and the solvent was then evaporated to give 635 mg of desired compound.

4.7 Synthesis of Piclidenoson
(3aS,4S,6R,6aR)-6-(6-((3-iodobenzyl)amino)-9H-purin-9-yl)-N,2,2-trimethyl-tetrahyd rofuro[3,4-d][1,3]dioxole-4-carboxamide (600 mg) was charged in RBF. To this was added equivalent amount of 1N aqueous HCl. The resulting slurry was heated at 50±5°C with stirring for approximately 8 hr. The batch was allowed to cool to approximately 40°C and then filtered. The resulting filtrate was stored in the cold room (2-8°C) overnight. To the filtrate chilled saturated aqueous NaHCO3 was added under stirring. The resulting white precipitate was stirred overnight. Filtered the precipitates using a nylon filter cloth and rinsed with water and dried to give desired piclidenoson.
Example-5: Preparation of solid dispersion of piclidenoson with HPC (Hydroxypropyl cellulose)
A mixture of piclidenoson and HPC (1:1˜10) was dissolved in methanol (30 mL) at 25°C and filtered the solution to make it particle free. The solvent was evaporated in rotavapour under reduced pressure at 50°C to obtain title compound.

CLAIMS:We claim:
1. Compounds of Formula II,

wherein, R1 is selected from hydrogen, carbon and silyl containing moieties;
G is selected from -CH2 and C=O;
R2, R3 are independently selected from hydrogen, substituted straight and branched alkyl chain, unsubstituted straight and branched alkyl chain, substituted and unsubstituted aryl, substituted and unsubstituted alkaryl, silyl containing moieties; and
optionally R2 and R3 together represents substituted and unsubstituted cyclic ring, wherein when R1 is hydrogen, the dotted bond is represented as a solid covalent bond and “N” is attached to aliphatic carbon with double bond.

2. The compounds as claimed in claim 1, wherein said compounds of Formula II is represented as compound of Formulae III, IV, VI and VII;
,
, and
wherein R1 is selected from hydrogen, carbon and silyl containing moieties; and
G is selected from -CH2 and C=O.

3. A process for the preparation of piclidenoson of Formula I by using compounds of Formula II as claimed in claim 1,
,
wherein said process comprising the steps of:
a) reacting compound of Formula VIIIa with compound of Formula IX in presence of a suitable solvent to get compound of Formula II,
,
wherein R1 is selected from hydrogen, carbon and silyl containing moieties;
G is selected from -CH2 and C=O;
R2, R3 are independently selected from hydrogen, substituted straight and branched alkyl chain, unsubstituted straight and branched alkyl chain, substituted and unsubstituted aryl, substituted and unsubstituted alkaryl, silyl containing moieties, and optionally R2 and R3 together represents substituted and unsubstituted cyclic ring, wherein when R1 is hydrogen, the dotted bond is represented as a solid covalent bond and “N” is attached to aliphatic carbon with double bond,
L is a leaving group; and
b) converting compound of Formula II to piclidenoson of Formula I.

4. A process for the preparation of piclidenoson, comprising the steps of:
a) adding 9H-purin-6-amine of Formula XIII and 3-iodobenzaldehyde in a suitable solvent to give 1-(3-iodophenyl)-N-(9H-purin-6-yl)methanimine of Formula XII,
; and
b) converting compound of Formula XII to piclidenoson of Formula I.

5. Compound of Formula XII,
,
wherein said compound of Formula XII is prepared by a process as claimed in claim 4.

6. The process as claimed in claims 3 and 4, wherein said piclidenoson is isolated with purity of 99.0% and above.

7. The process as claimed in claims 3 and 4, wherein said piclidenoson is substantially free of compounds of Formula II wherein said compound of Formula II is less than about 0.3% w/w.

8. A process for the preparation of amorphous solid dispersion of piclidenoson comprising the steps of:
a) providing a solution of piclidenoson in a suitable solvent;
b) providing atleast one pharmaceutically acceptable excipient in a solvent and adding the solution obtained in step a); and
c) isolating the amorphous solid dispersion of piclidenoson.

9. The process as claimed in claims 3, 4 and 8, wherein said suitable solvent is selected from the group comprising of toluene, xylene, dimethyl acetamide, dimethyl formamide, N-methyl pyrrolidine, dimethyl sulfoxide, hexamethyl phosphoramide, tetrahydrofuran, dioxane, methyl-tetrahydrofuran, diethyl ether, isopropyl ether, isobutyl acetate, methyl tert-butyl ether, acetone, methyl isobutyl ketone, methyl ethyl ketone, methanol, ethanol, methyl tert-butyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, t-butyl acetate, dichloromethane, ethylene dichloride, chloroform, dichlorobenzene, diethyl ether, isopropyl ether, heptane, hexane, pentane, water, C1-C5 straight and branched chain alcohols and mixture thereof.

10. A composition comprising piclidenoson as prepared by the process claimed in any of the preceding claims, along with atleast one pharmaceutical acceptable excipients.